PHASE-I TRIAL OF SUBCUTANEOUS RECOMBINANT HUMAN INTERLEUKIN-12 IN PATIENTS WITH ADVANCED RENAL-CELL CARCINOMA

Patients with advanced renal cell carcinoma were treated in a Phase I trial with escalating doses of recombinant human interleukin-12 (rHuIL -12) given on days 1, 8, and 15 of each 28-day cycle, Treatment in the initial dose scheme consisted of a fixed dose with dose levels of 0.1 , 0.5, and 1.0 mu g/kg given to cohorts composed of three or six patie nts. On the basis of the toxicity profile, a second scheme (up-titrati on) was undertaken wherein rHuIL-12 was escalated for each patient fro m week 1 to week 2, to a target dose given week 3 and thereafter; coho rt target dose levels were 0.5, 0.75, 1.0, 1.25, and 1.5 mu g/kg. Fift y-one patients were treated: 32 (63%) had prior cytokine therapy and 1 9 (37%) had received no prior systemic therapy. The maximum tolerated dose for the fixed dose scheme was 1.0 mu g/kg. Dose-limiting toxiciti es included increase in transaminase concentration, pulmonary toxicity , and leukopenia, The most severe toxicities occurred with the first i njection and mere milder upon further treatment, With the up-titration dose scheme, the maximum tolerated dose was reached at 1.5 mu g/kg, a nd dose-limiting toxicity consisted of an increase in serum transamina se levels. At the maximum tolerated dose of 1.5 mu g/kg, serum IL-12 l evels increased to a mean peak level of 706 pg/ml. Serum levels of IFN -gamma increased to a mean peak level of about 200 pg/ml at 24 h after the first maintenance dose of 1.5 mu g/kg. The best responses were as follows: one patient had complete response, 34 patients were stable, 14 patients showed progression, and 1 patient was inevaluable. In conc lusion, rHuIL-12 was relatively well tolerated when administered by s. c. injection, The recommended dose according to the up-titration sched ule of rHuIL-12 (mu g/kg) for Phase II trials was as follows: cycle 1, 0.1 (day 1), 0.5 (day 8), 1.25 (day 15); cycle 2 onwards, 1.25. Phase II trials of rHuIL-12 were initiated in previously untreated patients with renal cell carcinoma and in patients with melanoma.